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Formyl Peptide Receptor 2 Plays a Deleterious Role During Influenza A Virus Infections
Sergey Tcherniuk1, Nicolas Cenac2, Marjorie Comte3
1Institut National de la Santé et de la Recherche Médicale (INSERM), UMR_S 1062 INRA, UMR_INRA 1260, France Aix Marseille Université
Background:
The pathogenesis of influenza A virus (IAV) infections is a multifactorial process that includes the replication capacity of the virus and a harmful inflammatory response to infection. Formyl peptide receptor 2 (FPR2) emerges as a central receptor in inflammatory processes controlling resolution of acute inflammation. Its role in virus pathogenesis has not been investigated yet.
Methods:
We used pharmacologic approaches to investigate the role of FPR2 during IAV infection in vitro and in vivo.
Results:
In vitro, FPR2 expressed on A549 cells was activated by IAV, which harbors its ligand, annexin A1, in its envelope. FPR2 activation by IAV promoted viral replication through an extracellular-regulated kinase (ERK)-dependent pathway. In vivo, activating FPR2 by administering the agonist WKYMVm-NH2 decreased survival and increased viral replication and inflammation after IAV infection. This effect was abolished by treating the mice with U0126, a specific ERK pathway inhibitor, showing that, in vivo, the deleterious role of FPR2 also occurs through an ERK-dependent pathway. In contrast, administration of the FPR2 antagonist WRW4 protected mice from lethal IAV infections.
Conclusions:
These data show that viral replication and IAV pathogenesis depend on FPR2 signaling and suggest that FPR2 may be a promising novel strategy to treat influenza.
Insights
Formyl peptide receptor 2 (FPR2) activation by influenza A virus (IAV) worsens infection outcomes by promoting viral replication and inflammation. Blocking FPR2 signaling offers a potential therapeutic strategy for treating influenza.
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- Influenza A virus (IAV) pathogenesis involves viral replication and detrimental inflammatory responses.
- Formyl peptide receptor 2 (FPR2) is a key regulator of acute inflammation resolution.
- The role of FPR2 in viral pathogenesis remained unexplored.
Purpose of the Study:
- To investigate the role of FPR2 in IAV infection using pharmacological methods.
- To elucidate the mechanisms by which FPR2 influences viral replication and inflammation.
Main Methods:
- In vitro studies using A549 cells and IAV.
- In vivo studies in a mouse model of IAV infection.
- Pharmacological activation and inhibition of FPR2 and the ERK pathway.
Main Results:
- IAV activates FPR2 on A549 cells, enhancing viral replication via an ERK-dependent pathway.
- In vivo, FPR2 activation by WKYMVm-NH2 reduced survival and increased viral load and inflammation.
- Inhibition of the ERK pathway abolished the deleterious effects of FPR2 activation in vivo.
- FPR2 antagonism with WRW4 protected mice from lethal IAV infection.
Conclusions:
- FPR2 signaling is critical for IAV replication and pathogenesis.
- The deleterious effects of FPR2 in IAV infection are mediated through the ERK pathway.
- Targeting FPR2 represents a potential therapeutic strategy for influenza treatment.
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